Low levels of the brain peptide neurotensin (NT) have been linked to schizophrenia. Hence, stable NT receptor agonists that cross the blood brain barrier have significant potential for development as a new class of antipsychotics that may not have the adverse side effects associated with current drugs. During Phase I of this project, a proprietary NT agonist, ABS48, was developed that exhibits significant brain activity when IP and orally dosed, is active in 2 key rat models of schizophrenia at a "druggable" ED50 of 0.9 mg/kg IP., and does not exhibit side effects associated with other antipsychotics (antinociception and catalepsy) or tolerance to repeated dosing. In addition, an exhaustive structure-activity analysis leading to the discovery of ABS48 identified 18 more compounds that have the potential for enhanced potency and oral activity versus ABS48. Funding has been secured from a private foundation to support further preclinical studies of ABS48. The objective of this Phase II proposal is to secure the remaining funding necessary to define the best lead compound and complete preclinical studies on the lead to enable submission of an IND in preparation for clinical studies. In Specific Aim 1, the 18 new compounds will be benchmarked with ABS48 and each other to determine the best lead to commit to the preclinical studies. This will be performed at Argolyn and MUSC. In Specific Aim 2 synthesis of sufficient amounts of the peptide lead will be performed under GMP conditions to enable completion of the preclinical studies in Specific Aim 3, in which various bioavailability, toxicity and safety evaluations will be performed in rodents and dogs. Specific Aims 2 and 3 will be performed by Argolyn Bioscience through subcontracts with UCB Bioproducts and MPI Research, respectively. ABS48 has a unique pharmacologic profile and we believe that it (or a more active derivative identified from completion of Specific Aim 1) is the most promising NT-based compound for development as a novel antipsychotic.